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Introduction: Central precocious puberty (CPP) is characterized by the early onset of puberty and is associated with the critical processes involved in the pubertal switch. The puberty-related gene pool in the human genome is considerably large though few have been described in CPP. Within those genes, the genomic imprinting features of the MKRN3 and DLK1 genes add additional complexity to the understanding of the pathologic pathways. This study aimed to investigate the molecular etiology in the CPP cohort., Methods: Eighteen familial CPP cases were investigated by Sanger sequencing for five CPP-related genes; DLK1, KISS1, KISS1R, MKRN3, and PROKR2. Segregation analysis was performed in all patients with pathogenic variants. Using an ELISA test, the functional pathogenicity of novel variants was also investigated in conjunction with serum delta-like 1 homolog (DLK1) concentrations., Results: In three probands, a known variant in the MKRN3 gene (c.982C>T/p.(Arg328Cys)) and two novel variants in the DLK1 gene (c.357C>G/p.(Tyr119Ter) and c.67+78C>T) were identified. All three were inherited from the paternal allele. The individuals carrying the DLK1 variants had low detectable DLK1 levels in their serum., Conclusions: The frequencies were 5.5% (1/18) for MKRN3 11% (2/18) for DLK1, and none for either KISS1, KISS1R, and PROKR2. Low serum DLK1 levels in affected individuals supported the relationship between here described novel DLK1 gene variants with CPP. Nonsense nature of c.357C>G/p.(Tyr119Ter) and an alteration in the evolutionarily conserved nucleotide c.67+78C>T suggested the disruptive nature of the variant's compatibility with CPP., (© 2024. The Author(s).)

Parthenogenetically activated oocytes cannot develop to term in mammals due to lack of paternal gene expression. Disruption of imprinted gene expression and DNA methylation status in parthenogenetic fetuses has been reported in mice and pigs, but not in rabbits. In this study, the genomic imprinting status of the paternally expressed genes Neuronatin (NNAT), Nucleosome assembly protein 1-like 5 (NAP1L5), and Makorin ring finger protein 3 (MKRN3) was compared between rabbit parthenogenetic (PA) and normally fertilized fetuses (Con) using quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR (BSP). The results revealed a significantly reduced expression of NNAT, NAP1L5, and MKRN3 in rabbit PA fetuses compared with Con fetuses (p<0.05). In addition, the BSP results demonstrated hypermethylation in the differentially methylated regions (DMRs) of NNAT, NAP1L5, and MKRN3 in rabbit PA fetuses. Taken together, these results suggest that hypermethylation of DMRs is associated with decreased NNAT, NAP1L5, and MKRN3 expression, which may be responsible for developmental failure of rabbit PA fetuses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The productivity of beef cows depends on early reproduction traits such as puberty and has an economic impact on the efficiency of production system. Imprinted genes modulate many important endocrine processes such as growth, the onset of puberty and maternal reproductive and behavior. The role of imprinted genes in puberty is a challenging subject since they show the reciprocal role of maternal and paternal genomes in progeny. Although, there are evidences of the involvement of imprint genes in puberty in human, the role of this type of genes in the onset of puberty in cattle has not been studied yet. Here we examined the expression of 27 imprinted genes in pre and post puberty in a bovine model to find differentially expressed imprinted genes in maternal-paternal purebreds and reciprocal crosses across eight tissues and discussed the task of these genes in this crucial process of development and in onset of puberty. DLK1 and MKRN3 that previously described as cause of the central precocious puberty (CPP) in human were differentially expressed in this study. Functional annotation analysis of differentially imprinted genes in different tissues showed significant biological processes of cellular response to growth factor stimulus, response to growth factor, response to parathyroid hormone, developmental growth and the importance of alternative splicing. The results of this study have implications in understanding the role of imprinted genes in the onset of puberty in cattle. [ABSTRACT FROM AUTHOR]

Central precocious puberty (СPP) is caused by premature reactivation of the hypothalamic–pituitary–gonadal axis. Genetic, epigenetic, and environmental factors play a crucial role in determining the timing of puberty. In recent years, the KISS1, KISS1R, MKRN3, and DLK1 variants have been identified as hereditary causes of CPP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic modifications that alter the expression of these genes are also considered as a cause of precocious puberty. With the progression of CPP, epigenetic factors such as DNA methylation, posttranslational modifications of histones and noncoding RNAs can mediate the relationship between the influence of genetic variants and the environment. CPP is also associated with other short- and long-term adverse health effects. This is the basis for research aimed at understanding the genetic and epigenetic causes of СPP. The purpose of this review is to summarize the published data on the molecular genetic and epigenetic mechanisms of the formation of СPP. [ABSTRACT FROM AUTHOR]

Central precocious puberty (CPP) is a condition in which the hypothalamus--pituitary--gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R, that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1, MKRN3, DLK1, and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future. [ABSTRACT FROM AUTHOR]